Stress Tied to Tough Time Conceiving

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An increase in salivary alpha-amylase production by the parotid gland occurs in response to norepinephrine secreted into the bloodstream during time of stress.

Increased levels of alpha-amylase were associated with an increase in the risk of infertility.

High levels of the stress biomarker salivary alpha-amylase were associated with a greater likelihood of delayed pregnancy in women trying to conceive, according to researchers.

Women with the highest levels of alpha amylase at study entry, and following their first observed study menses, were twice as likely to fail to conceive over 12 months as women with the lowest levels of the stress biomarker (relative risk=2.07, 95% CI 1.04-4.11), reported Courtney Lynch, PhD, MPH, of The Ohio State University in Columbus, and colleagues, in Human Reproduction online.

This is the first U.S. study to show an association between stress -- as measured by activation of the sympathetic adrenomedullary (SAM) pathway -- and early infertility, the authors stated.

"We know that about one-third of infertility has an unknown cause," Lynch told MedPage Today. "This tells us that by taking steps to reduce stress before attempting to become pregnant, many of these women may be able to optimize their fertility and avoid medical treatment. Stress may just be one small piece of the bigger picture in infertility, but I think it is a particularly interesting piece because it is something that a woman has the potential to change on her own."

Until recently, most of the research examining stress and infertility has been from cross-sectional studies of couples seeking treatment for infertility, which were complicated by the fact that "the directionality of the association could not be determined," her group wrote.

In a 2011 study done in a cohort in the U.K., Lynch and colleagues reported a prospective association between increased alpha-amylase and a 12% reduction in the day-specific probability of pregnancy, but this did not translate into a longer time-to-pregnancy (TTP), probably because the sample size was small at 274 women, Lynch said.

The current research was done using data collected from 2005 to 2009 as part of the Longitudinal Investigation of Fertility and the Environment (LIFE) Study, which enrolled 501 couples in Michigan and Texas at the time that they were discontinuing contraception for the purposes of becoming pregnant.

The couples were followed for up to 12 months as they tried to conceive and through pregnancy if it occurred. A total of 401 (80%) of the couples completed the study protocol and 373 (93%) had complete data available for the analysis.

After enrollment, the women collected saliva samples first thing in the morning, and then following their first observed study menses for the measurement of cortisol and alpha-amylase. The women were told to collect the samples before eating, drinking, smoking, or brushing their teeth.

The authors explained that "for the SAM system, norepinephrine is secreted into the bloodstream, which eventually results in an increase in salivary alpha-amylase production by the parotid gland."

TTP was measured in cycles using journals and fertility monitors. Women's daily journals also recorded bleeding, intercourse, periodic use of contraception, fertility monitor results, pregnancy test results, and other lifestyle data such as smoking and coffee consumption. Women were also asked to rate their daily stress level from 1 to 4, with 1 representing "almost no stress" and 4 representing "a lot of stress."

The women had no known fertility problems when enrolled in the study and they had just started trying to conceive, suggesting that everyday stress, and not the specific stress associated with trying to become pregnant, affected their fertility, Lynch and colleagues wrote.

Among the 401 women who completed the protocol, 347 (87%) became pregnant and 54 (13%) did not over the course of a year.

No association was found between salivary cortisol levels and conception at 12 months, but after adjustment for age and several other factors known to influence fertility, women with the highest alpha-amylase had a 29% reduction in fecundity (longer time to pregnancy), compared with women in the lowest, expressed as a fecundability odds ratio (FOR 0.71, 95% CI 0.51-1.00. P<0.05).

In addition to the twofold increase in infertility risk and 29% reduction in fecundity among the women with highest and lowest tertiles of alpha-amylase levels, the analysis revealed that women in the middle tertile of salivary alpha-amylase had a 7% decreased odds of pregnancy after adjustment (FOR 0.93, 95% CI 0.68-1.29).

Women had similar times to pregnancy until around cycle five, at which time those in the highest tertile of alpha-amylase began to have lower pregnancy probabilities.

One study limitation cited was the inability to collect repeated saliva samples and perceived stress questionnaire data throughout the follow-up period. This made it impossible to determine if stress levels increased as the time to pregnancy increased.

Reproductive endocrinologist Tomer Singer, MD, of Lenox Hill Hospital in New York City, said other limitations included the relatively small sample size and homogeneity of the study cohort (83% were both non-Hispanic whites and college graduates), and the fact that 51% of the women had given birth prior to entering the study.

Singer also noted that the failure to show an association between cortisol levels and times to pregnancy, and the fact that several previous studies have failed to show a correlation between alpha-amylase levels and stress, makes the clinical implications of the research difficult to interpret.

The measurement of salivary alpha-amylase is considered a research assay only, and the test is not likely to be used in the clinical setting, he said.

"Despite the limitations, this is one of the first studies to measure what we have known in infertility for a very long time," Singer told MedPage Today. "We see it in the practice setting all the time. Stress affects fertility. We just haven't been able to tell our patients how."

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

The researchers reported no relevant conflicts of interest.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

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